Intermediates useful for the preparation of antihistaminic...

Details Intermediates useful for the preparation of antihistaminic... Intermediates useful for the preparation of antihistaminic...

1994-07-14

2001-06-05

Chang, Ceila (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S240000

Reexamination Certificate

active

06242606

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is related to novel intermediates which are useful in the preparation of certain piperidine derivatives which are useful as antihistamines, antiallergy agents and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981, U.S. Pat. No. 4,285,958, Apr. 25, 1981 and U.S. Pat. No. 4,550,116, Oct. 29, 1985].
These antihistaminic piperidine derivatives can be described by the following formula:
wherein
W represents —C(═O)— or —CH(OH)—;
R
1
represents hydrogen or hydroxy;
R
2
represents hydrogen;
R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R
3
is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R
1
and R
2
are taken together to form a second bond between the carbon atoms bearing R
1
and R
2
or where R
1
represented hydroxy, m is an integer 0.
SUMMARY OF THE INVENTION
The present invention provides novel intermediates useful for the preparation of certain antihistaminic piperidine derivatives of formula (I)
wherein
W represents —C(═O)— or —CH(OH)—;
R
1
represents hydrogen or hydroxy;
R
2
represents hydrogen; or
R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R
3
is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R
1
and R
2
are taken together to form a second bond between the carbon atoms bearing R
1
and R
2
or where R
1
represented hydroxy, m is an integer 0.
These novel intermediates are described by the following formulas:
wherein
A is a hydrogen or hydroxy; and
R
5
is H, —CH
2
OD wherein D is hydrogen, acetate or benzoate, —CHO, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
A is a hydrogen or hydroxy; and
R
5
is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
A is a hydrogen or hydroxy; and
R
5
is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R
5
is H, CH
2
OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl, I, CN, —COOH or —CONR
6
R
7
wherein R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R
5
is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy;
R
5
is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5; and
A is a hydrogen or hydroxy.
wherein A is a hydrogen or hydroxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R
5
is H, CH
2
OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy; and
individual optical isomers thereof.
wherein
W represents —C(═O)— or —CH(OH)—;
R
1
represents hydrogen or hydroxy;
R
2
represents hydrogen; or
R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R
5
is H, Br, Cl, I, CN or —CONR
6
R
7
wherein R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy;
A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R
1
and R
2
are taken together to form a second bond between the carbon atoms bearing R
1
and R
2
or where R
1
represented hydroxy, m is an integer 0.
In addition, the present invention provides novel processes for preparing the antihistaminic piperidine derivatives of formula
wherein
W represents —C(═O)— or —CH(OH)—;
R
1
represents hydrogen or hydroxy;
R
2
represents hydrogen; or
R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R
3
is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R
1
and R
2
are taken together to form a second bond between the carbon atoms bearing R
1
and R
2
or where R
1
represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a cumene compound of the formula
wherein A is as defined above with a &ohgr;-halo compound of the formula
wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a &ohgr;-halo cumylketone compound;
(b) reacting the &ohgr;-halo cumylketone compound with a suitable halogenating agent to give a &ohgr;-halo-halocumylketone compound;
(c) reacting the &ohgr;-halo-halocumylketone compound compound with a suitable cyanating agent to give a &ohgr;-halo-cyanocumylketone compound;
(d) reacting the &ohgr;-halo-cyanocumylketone compound with an appropriate straight or branched C
1
-C
6
alcohol in the presence of a suitable anhydrous acid to give a &ohgr;′-halo-&agr;′-keto-&agr;,&agr;-dimethylphenylacetic acid imidate compound;

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